2-ammonio-ethyl 3-ammoniopropionates



nite States Patent -'ii ice 2,810,743 Patented Oct. 22, 1957 2,810,743 Z-AMMONIO-ETHYL 3-AMMONIOPROPIONATES Arthur R. Williams, Berkeley, and John Hidalgo, Richmond, Califi, assiguors to Cutter Laboratories, Inc., Berkeley, Calif., a corporation of California No Drawing. Application June 28, 1954,

Serial No. 439,890

7 Claims. (Cl. 260-482) wherein R and R are methyl or ethyl, which may be the same or different, and wherein X and X are stable, nontoxic anions.

It has been proposed recently that in many surgical procedures, it would be exceedingly advantageous to have an agent available which would produce a marked but temporary drop in blood pressure without any other physiological effects, and which would be so short acting that the blood pressure would return to normal within a few minutes after the administration of the agent was stopped. With such an agent available, the surgeon could begin the administration of the drug just before he was required to cut across a venous bed, thus reducing the intensity of the bleeding. While the administration was being continued, the surgeon could apply conventional hemostats, then cease the administration of the drug, and with the immediate rise in blood pressure, observe, by renewed bleeding any bleeding points that were missed. The use of such a drug should markedly reduce the loss of blood during complicated surgery as well as reduce the time of the surgical procedures.

Since this concept was proposed, several hypotensive drugs have been tried but so far all have failed to completely satisfy the requirements.

Alpha 1,3 dibenzyldecahydro 2 oxo imidazo [c]thieno-[1,2-a] -thiolium d-camphor sulfonate, known in the art as Arfonad, is a fairly short acting hypotensor, and has been tried, but it requires so near the lethal dose to produce the required lowering of the blood pressure that it is not considered a safe drug for an elective procedure; also, when administration is ceased, six to eight minutes are required for the blood pressure to return to normal. Hexamethonium, one of the most powerful hypotensors, is very efiective in lowering the blood pressure. However, its action persists for at least twenty minutes after injection has been stopped and it is therefore completely unsuitable for this purpose. To date, no one has produced a compound which is safe to use and which will cause a controllable drop in blood pressure.

During the course of a general syntheticprogram, a group of compounds containing two quaternary nitrogen groups separated by four to six carbon atoms and containing one ester group has been prepared which individually shows striking differences physiologically but two of which have proven of value in controlled hypotension.

2 (trimethylammonio)ethyl 3 (trimethylammonio)- propionate diiodide was synthesized and proved to be a very potent and short acting hypotensor, but extremely cholinergic. Among the cholinergic side efiects, it produced an intense salivation which would be dangerous in an anesthetized patient. This compound was described by Fusco et al. (Gass. Chim. Ital. 79, 836-48, 1949) who were searching for drugs with curare-like properties. We also synthesized the corresponding dichloride (M. P. 213- 214 degrees) and found its pharmacological properties to be quantitatively the same as those of the diiodide, except that the dichloride was more potent, proportional to its lower molecular weight.

The compounds which are the subject of this invention, 2 (dimethylethylammonio)ethyl 3 (dimethylethylammonio)propionate dianion and 2 (diethylmethylammonio)ethyl 3 (diethylmethylammonio)propionate dianion, have proven to be extremely potent and short acting hypotensors with a methylethylammonio)ethyl 3 (dimethylethylammonio)- propionate diiodide, in an intravenous dose of 0.1 milligram per kilogram of body weight causes a rapid fall in blood pressure of 50-60 millimeters of mercury absolute, and the blood pressure returns to normal within 30-60 seconds after administration of the drug is interrupted. The mechanism of the hypotension is apparently by ganglionic blockade. By even rapid injection, salivation,

or other cholinergic effects, is not detectable except at a: dosage of 0.2 milligram per kilogram. The MLD in mice is 50 milligrams per kilogram, which olfers a very wide margin of safety. 2 (diethylmethylammonio)- ethyl 3 (diethylmethylammonio) propionate diiodide shows no cholinergic activity and is slightly more toxic, the MLD in mice being 37.5 milligrams per kilogram. In other words, they meet the criterion for use in controlled surgical hypotension, and are preferably used in the form of the dichlorides.

Schueler et al. (Science 113, 512-514, 1951) described 2 (triethylammonio)ethyl 3 (triethylammonio)propionate dibromide which meets some of the requirements outlined above; except that its hypotensive action is so weak as to be valueless for use as a controlled surgical hypotensive agent. As pointed out in Schuelers more recent publication (I. Am. Pharm. Assoc., Sci. Ed., 43, 98, 1954), the dose required to produce a significant hypotension even when supplemented by the technic of postural hypotension was 4-10 milligrams per kilogram. The corresponding diiodide synthesized by us was found to be an extremely weak hypotensor.

The compounds of the present invention are colorless crystals which are water and methanol-soluble.

Preparation of the compounds of the present invention may be readily accomplished by the interaction of a suitable 2 haloethyl 3 halopropionate and dimethylethylamine or diethylmethylamine, wherein the halogen of the ester is chlorine, bromine, or iodine. The reaction is usually accomplished in the presence of as, for example, chloroform, dioxane, acetone, et cetera, and temperatures between about ten degrees centigrade and degrees centigrade may be employed. The rerecovering the diammonio While both of the above procedures result in the prep-" aration of halide anions, the present invention also com wide margin of safety and little or no cholinergic action. For example, the 2-(direaction product is i 3 templates other stable, non-toxic anions, such as,'for example, the nitrate, sulfate, phosphate, acetate, bitartrate, citrate, borate, formate, lactate, oxalate, propionate, et cetera. These anions may be substituted for ,the halide anion by treatmentof the halide-containirig material with;

a salt of the appropriate acid which will form an insoluble halide, or by the use of ion exchange resinsin conventional manner.

' The following preparations. may be used to prepare certain intermediates for the compounds of the present invention. 7

PREPARATION 1.--2-IODOETHYL S-IODQPR PIQNATE 100 milliliters'of saturated sodium bicarbonate solution, 100 milliliters of ten percent aqueous sodium thiosulfate,

and dried over magnesium sulfate. 'The ether was removed by distillation to yield 21 grams (51 percent of the theoretical yield) of a nearly colorless liquid, 2-iodoethyl 3-iodopropionate, having a boiling point of 100-109 degrees centigrade at one millimeter of mercury pressure absolute. V

PREPARATION 2.-2-DIETHYLAMINOETHYL 3-DIETHYL- AMINOPROPIONATE DIHYDROCHLORIDB To a solution of33 grams (0.093 mole) of 2-iodoethyl 3-iodopropionate in '200 milliliters of dry benzene was added 27.3 grams (0.373 mole) of diethylamine. This mixture was allowed to stand at room temperature for four days, cooled in an ice bath, and the crystals which formed were removed by filtration. The filtrate was concentrated to 100 milliliters. on a steam bath, chilled in an ice bath, and the resulting precipitate removed by filtration. (0.30 mole) of acetone. moved by filtration and recrystallized twice in 125-milliliter portions'of methanol. There was thus obtained 8.7 grams of 2-diethylaminoethyl 3-diethylaminopropionate dihydrochloride, melting at 221.5 degrees centigrade,

hydrogen chloride in' 500 milliliters of when the rate of heating is one degree per minute from 215 degrees centigrade.

Calculated: C13H3oCl2N202: C, 49.21; H, 9.53; (:1, 22.35. Found: C, 48.84; H, 9.10; Cl, 22.21.

The following examples illustrate procedures whereby the compounds of the present invention may be prepared, but are not to be construed as limiting the invention thereto.

Example 1 Tea solution of 10.0 grams (0.028 mole) of Z-iodoethyl 3-iodopropionate in fifty milliliters of chloroform was added 5.0 grams (0.068 mole) of dimethylethylamine. This mixture was'allowed to stand at room temperature for three days, and the excess chloroform decanted from the pale yellow oil which resulted. The oil was dissolved in 25 milliliters of refluxing methanol, and five milliliters of ether added. .The mixture was placed in an ice chest. After three days, the colorless rosettes which formed'we're separated by filtration. After recrystallization there was thus obtained 4.6 grams of colorless crystals, 2-(dimethylethylarnmonio) ethyl ,3 (dimethylethylammonio)propionate diiodide, having a melting point of 177-179 degrees centigrade.

AnaZysis.-'Calculated: CrHsoIzNzOzHzOz' C, 30.13; H, 6.22; I, 48.98. Found: C, 30.43; H, 5.29; I, 48.90.

In a manner similar to that of the foregoing Example 1, diethylmethylamine may be substituted for the dimethyl- The filtrate was then treated with 10.9 grams The colorless solid which precipitated was re-.

. 4 ethylamine to prepare Z-(diethylmethylammo'nio)ethyl 3-(diethylmethylammonio)propionate diiodide.

Example 2 (0.05 mole) of potassium carbonate, andthe oil which i separated was extracted with three fifty-milliliter portions of ether. The combined ether extracts weredried over anhydrous sodium sulfate, filtered, and the ether evaporated. The resulting colorless oil was dissolved in 25 milliliters of acetone and six grams (0.04 mole) of methyl iodide added. After standing for one day at room tem- 1 perature, crystals were obtained and these crystals re-,

moved by filtration. There was thus obtained 4.9 grams of colorless crystals, which after two recrystallizations Y from a mixture of methanol, acetone and ether, yielded dense colorless crystals, 2 (diethylmethylammonio)ethyl 3-(diethylmethylammonio)propionate diiodide, having .a melting point of 184-185 degrees Centigrade.

Analysis.-Calculated: C15H34I2N2O2: C, 34.10; H, 6.49; I, 48.05. Found:

In the manner of the foregoing examples, other compounds having dilferent halogen anions may be prepared by substituting methylbromide or methylchloride for the methyl iodide of Example 2, or by bromine for the iodine contained in the starting material of Example 1. Alternatively, the iodide can be converted to the chloride or bromide by transhalogenation us ng ion exchange resins in conventional manner.

Example 3 A solution of one part of Z-(diethylmethylammonio) ethyl 3-(diethylmethylammonio)propionate diiodide in ten parts of water was treated with 0.65 part of silver nitrate in ten parts of water. The silver iodide which formed was removed by filtration, and the water removed from the filtrate by distillation under reduced'pressure' Example 4 A solution of 2.5 parts of 2-(dimethylethylammonio) ethyl 3-(dimethylethylammonio)propionate diiodide in fifty parts of methanol was treated with 1.7 part of silver nitrate in fatty parts of methanol. which precipitated was parts of ether added to less, viscous oil. refluxing V isoprop anol. which were separated and recrystallized from isopropanol. There was thus obtained 2-(dimethylethylammonio)- ethyl 3-(dimethylethylammonio)propionate dinitrate, as colorless crystals, melting at 162 degrees Centigrade.

Analysim-Calculated for C13H30N40a2 8.17. 'Found: C, 41.7;H, 7.9;

In a manner similar to that of the foregoing Examples 3 and 4, other anions, such as, for example, the sulfate, phosphate, acetate, et cetera, may be substituted for the the filtrate, precipitating a colorhalide or nitrate, by the procedure of the examples or a by the use of ion exchange resins, in conventional manner. It was very surprising that the compounds. of the present invention have relatively little cholinergic activity,

.since closely related compounds, 2-(trimethylammonio)- ether and two portions of iso The silver iodide. removed by filtration and 200 This oil was separated and dissolved in Upon cooling, crystals formed,

filed application Serial No.

1954, now abandoned.

Various modifications may be made in the compounds of the present invention Without departing from the spirit or scope thereof, and it is to be understood that we limit ourselves only as defined in the appended claims.

We claim:

1. A compound having the formula:

415,974, filed March 12,

3. 2-(diethylmethylammonio)ethyl 3 ammonio)propionate dihalide, wherein lected from the group consisting of and iodine.

4. Z-(diethylmethylarnmonio)ethyl 3 (diethylmethylammonio)propionate dinitrate.

5. Z-(dimethylethylammonio)ethyl 3 (dimethylethylammonio)propionate dinitrate.

6. 2-(dimethy1ethylammonio)ethyl 3 (dimethylethylammonio)propionate diiodide.

7. 2-(diethylmethylammonio)ethyl 3 (diethylmethylammonio)propionate diiodide.

(diethylmethylthe halogen is sechlorine, bromine References Cited in the file of this patent Schueler et a1.: Science, vol. 113 (1951), 512-4. 

1. A COMPOUND HAVING THE FORMULA: 